Drug-induced activation of the reelin signaling system

ABSTRACT

Disclosed herein are compounds for activating the Reelin signaling system for the treatment of neurological disorders. Further provided are compounds and methods for activating a lipoprotein receptor, such as ApoER2 or VLDLR.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/577,072 filed Oct. 25, 2017, and U.S. Provisional PatentApplication No. 62/592,340 filed Nov. 29, 2017, each of which isincorporated herein by reference in its entirety.

FIELD

This disclosure relates to compounds for activating the Reelin signalingsystem for the treatment of neurological disorders.

INTRODUCTION

Activation of Apolipoprotein receptor 2 (ApoER2) and the very-lowdensity lipoprotein receptor (VLDLR) are involved in a myriad ofneuronal activities in both the developing and adult central nervoussystem. These receptors are activated through the binding andinternalization of the Reelin protein. The mode of action for thisreceptor activation is through dimerization or clustering of ApoER2 orVLDLR, which leads to the phosphorylation and activation of theintracellular adapter protein Dab1.

Reelin is expressed in the brain and in peripheral tissues. The lack ofReelin expression is associated with neurological disorders andinability of organs to self-repair. Administering Reelin as atherapeutic in its endogenous absence is problematic due to its size.Full-length Reelin is a 450 kDa protein that is cleaved to smallerprotein fragments. The 180 kDa protein fragment may be the majorfragment that activates the Reelin signaling system, but it is too largeto pass the blood-brain-barrier (BBB). Soluble small molecules that caneasily pass the BBB and have the same mechanism of action as Reelincould be more readily developed as a therapeutic. There is a need forsmall molecule agonist compounds that can be used in place of Reelin toactivate the Reelin signaling system.

SUMMARY

In an aspect, the disclosure relates to methods of treating a disease ordisorder in a subject in need thereof, the method comprisingadministering to the subject an agonist of a lipoprotein receptor.

In a further aspect, the disclosure relates to methods of improvingcognitive function in a subject in need thereof, the method comprisingadministering to the subject an agonist of a lipoprotein receptor.

Another aspect of the disclosure provides methods of increasingdendritic spine density in a subject in need thereof, the methodcomprising administering to the subject an agonist of a lipoproteinreceptor.

Another aspect of the disclosure provides methods of improvingassociative learning in a subject in need thereof, the method comprisingadministering to the subject an agonist of a lipoprotein receptor.

Another aspect of the disclosure provides methods of improving spatiallearning in a subject in need thereof, the method comprisingadministering to the subject an agonist of a lipoprotein receptor.

Another aspect of the disclosure provides methods of improving long-termpotentiation of neurons in a subject in need thereof, the methodcomprising administering to the subject an agonist of a lipoproteinreceptor.

In some embodiments, the lipoprotein receptor is selected from ApoER2and VLDLR. In some embodiments, the disease or disorder is of thecentral nervous system. In some embodiments, the disease or disorder isa developmental disorder, a cognitive disorder, a degenerative disorder,a neuropsychiatric disorder, or brain injury. In some embodiments, thedevelopmental disorder is Lissecephaly. In some embodiments, thecognitive disorder is selected from Angelman Syndrome and schizophrenia.In some embodiments, the degenerative disorder is Alzheimer's disease.In some embodiments, the neuropsychiatric disorder is selected fromschizophrenia and bipolar disorder. In some embodiments, the braininjury is traumatic brain injury (TBI). In some embodiments, the diseaseor disorder is selected from Lissecephaly, fragile X syndrome, William'ssyndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism,ischemia, hypoxia, Alzheimer's disease, Reelin deficiency,schizophrenia, bipolar disorder, neurodegeneration, traumatic braininjury, mental retardation, dementia, bipolar disorder, and stroke.

Another aspect of the disclosure provides methods of treating a centralnervous system disease or disorder by activating the Reelin signalingsystem in a subject in need thereof, the method comprising administeringto the subject an effective amount of a small molecule agonist of alipoprotein receptor.

In some embodiments, the agonist comprises a compound according toFormula I′:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.

Another aspect of the disclosure provides methods of activating alipoprotein receptor in a subject in need thereof, the method comprisingadministering to the subject a compound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;

or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof; wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl. In some embodiments, the lipoprotein receptor is selected fromApoER2 and VLDLR.

Another aspect of the disclosure provides an agonist of ApoER2 or VLDLR,wherein the agonist is a compound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;

or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.

Another aspect of the disclosure provides a compound according toFormula I′:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;

or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.

Another aspect of the disclosure provides a pharmaceutical compositioncomprising a compound as detailed herein. In some embodiments, thecomposition further comprises a carrier for oral, intranasal,intravaginal, transdermal, intravenous, intraarterial, intratumoral,intraperitoneal, or topical administration.

In some embodiments, the agonist or compound is of Formula I′, and R¹ ismethoxy, OH, or isopropyl. In some embodiments, the agonist or compoundis of Formula I′, and Z and Y together form a heteroaryl ring. In someembodiments, the agonist or compound is of Formula I′, and Z and Ytogether form benzimidazole. In some embodiments, the agonist orcompound is of Formula I′, and X is phenyl substituted with (R²)_(m). Insome embodiments, at least one R² is methyl. In some embodiments, atleast one R² is Cl or I. In some embodiments, the agonist or compound isof Formula I, and R¹ is methoxy, OH, or isopropyl. In some embodiments,the agonist or compound is of Formula I, and Z and Y together form aheteroaryl ring. In some embodiments, the agonist or compound is ofFormula I, and Z and Y together form benzimidazole. In some embodiments,the agonist or compound is of Formula I, and X is phenyl substitutedwith (R²)_(m). In some embodiments, at least one R² is methyl. In someembodiments, at least one R² is Cl or I. In some embodiments, theagonist or compound is of Formula II, and R¹ is C₁₋₄ alkyl. In someembodiments, R¹ is methyl, ethyl, or isopropyl. In some embodiments, theagonist or compound is of Formula II, and R² is Cl or I. In someembodiments, the agonist or compound is of Formula I′, and R¹ is Cl, nis 2, W is O, Q is CH₂, Z is C═O, Y is NH, and X is phenyl substitutedwith (R²)_(m), wherein R² is Cl and m is 1. In some embodiments, theagonist or compound is of Formula II, and R¹ is methyl, ethyl, orisopropyl. In some embodiments, the agonist or compound is of FormulaII, and R¹ is isopropyl. In some embodiments, n is 1 or 2. In someembodiments, the agonist or compound is of Formula III, and R² is Cl. Insome embodiments, the agonist or compound is of Formula III, and R² isCl, R¹ is isopropyl, and n is 1. In some embodiments, the agonist orcompound is selected from the following:

or a pharmaceutically acceptable salt thereof.

The disclosure provides for other aspects and embodiments that will beapparent in light of the following detailed description and accompanyingfigures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a dose response curve for assessing luciferase activity toexamine ApoER2 dimerization. FIG. 1B is a time course for the luciferaseassay comparing Relact02 and control. FIG. 1C is a time course for theluciferase assay comparing Relact02, Reelin, and control.

FIG. 2 is gel showing expression of ApoER2 and phosphorylation of DAB-1in primary neuronal cell cultures upon administration of Relact02 orcontrol.

FIG. 3 is a schematic of the ApoER2 Clustering Assay. The ApoER2clustering assay uses the co-transfection of ApoER2 fusion proteins thatexpress either the C- or N-terminal of the luciferase enzyme (A″). UponReelin fragment binding, receptor clustering results in activeLuciferase and detectable fluorescence (B″). Controls includednon-transfected Hek293 cells. Results are average+/−SEM; n=9-15 assaysper fragment

FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D are graphs of luminescence versuscompound concentration according to the ApoER2 luciferase assay forRelact02 (FIG. 4A), Relact03 (FIG. 4B), Relact04 (FIG. 4C), and Relact05(FIG. 4). Renilla is a constant florescence enzyme that controls for thequantification of viable cells in the 96-well plate. The ratio offirefly/renilla shows firefly florescence within a quantifiable numberof cells in culture.

FIG. 5A and FIG. 5B are time course graphs for Relact02 (FIG. 5A) andRelact03 (FIG. 5B) in the ApoER2 luciferase assay using the optimumconcentration as determined in the Dose Response Curves (FIG. 4A andFIG. 4B, respectively).

FIG. 6A is a schematic diagram showing how Reelin signaling can modifysynaptic function through the activation of downstream effectors ERK andAKT (through PI3K), with the legend in FIG. 6B.

FIG. 7A, FIG. 7B, FIG. 7C, and FIG. 7D are graphs showing in vitroactivation of Reelin signaling pathways with Relact02 (FIG. 7A),Relact03 (FIG. 7B), Relact04 (FIG. 7C), and Relact05 (FIG. 70).

FIG. 8 are graphs showing the effect of Relact02 on levels of pDab1,pERK/tERK, and pAKT/AKT in adult hippocampal slices. These testsrepresent a greater neuronal complexity and indicate an ability tosignal in an in vivo system.

FIG. 9A is a graph of Firefly/Renilla fluorescence for Relact02 analogsaccording to the ApoER2 luciferase assay at 10 μM analog concentrationand 60 minutes. FIG. 9B is a graph of Firefly/Renilla fluorescence forvarious concentrations of a Relact02 analog (Compound ID 5260146)according to the ApoER2 luciferase assay.

DETAILED DESCRIPTION

Described herein are compounds for activating a Reelin signaling pathwayand methods of administering the compounds for treating a disease ordisorder. Reelin signaling disruption is a factor in a variety ofneurological and neurodegenerative disorders. The compounds detailedherein are agonists that may act upon the lipoprotein receptor system ina manner similar to Reelin for use as therapeutics in the improvement ofcognitive function as well as the treatment of neurological andneurodegenerative disorders. The compounds may be administered to asubject for the treatment of a variety of disorders of the centralnervous system and improving cognitive function.

1. DEFINITIONS

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. In case of conflict, the present document, includingdefinitions, will control. Preferred methods and materials are describedbelow, although methods and materials similar or equivalent to thosedescribed herein can be used in practice or testing of the presentinvention. All publications, patent applications, patents and otherreferences mentioned herein are incorporated by reference in theirentirety. The materials, methods, and examples disclosed herein areillustrative only and not intended to be limiting.

The terms “comprise(s),” “include(s),” “having,” “has,” “can,”“contain(s),” and variants thereof, as used herein, are intended to beopen-ended transitional phrases, terms, or words that do not precludethe possibility of additional acts or structures. The singular forms“a,” “and,” and “the” include plural references unless the contextclearly dictates otherwise. The present disclosure also contemplatesother embodiments “comprising,” “consisting of,” and “consistingessentially of,” the embodiments or elements presented herein, whetherexplicitly set forth or not.

For the recitation of numeric ranges herein, each intervening numberthere between with the same degree of precision is explicitlycontemplated. For example, for the range of 6-9, the numbers 7 and 8 arecontemplated in addition to 6 and 9, and for the range 6.0-7.0, thenumber 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 areexplicitly contemplated.

The term “about” as used herein as applied to one or more values ofinterest, refers to a value that is similar to a stated reference value.In certain aspects, the term “about” refers to a range of values thatfall within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greaterthan or less than) of the stated reference value unless otherwise statedor otherwise evident from the context (except where such number wouldexceed 100% of a possible value).

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this disclosure, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito, 1999; Smith and March March's Advanced OrganicChemistry, 7^(th) Edition, John Wiley & Sons, Inc., New York, 2013;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., NewYork, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd)Edition, Cambridge University Press, Cambridge, 1987; the entirecontents of each of which are incorporated herein by reference.

The term “alkoxy” or “alkoxyl” as used herein, refers to an alkyl group,as defined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of alkoxy include, but are notlimited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 20 carbon atoms. The term “loweralkyl” or “C₁₋₆ alkyl” means a straight or branched chain hydrocarboncontaining from 1 to 6 carbon atoms. The term “C₁₋₄ alkyl” means astraight or branched chain hydrocarbon containing from 1 to 4 carbonatoms. The term “C₁₋₃ alkyl” means a straight or branched chainhydrocarbon containing from 1 to 3 carbon atoms. Representative examplesof alkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkenyl” as used herein, means an unsaturated hydrocarbonchain containing from 2 to 20 carbon atoms and at least onecarbon-carbon double bond.

The term “alkynyl” as used herein, means an unsaturated hydrocarbonchain containing from 2 to 20 carbon atoms and at least onecarbon-carbon triple bond.

The term “alkoxyalkyl” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein.

The term “arylalkyl” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein.

The term “alkylamino,” as used herein, means at least one alkyl group,as defined herein, is appended to the parent molecular moiety through anamino group, as defined herein.

The term “alkylene” as used herein, refers to a divalent group derivedfrom a straight or branched chain hydrocarbon of 1 to 10 carbon atoms,for example, of 2 to 5 carbon atoms. Representative examples of alkyleneinclude, but are not limited to, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,and —CH₂CH₂CH₂CH₂CH₂—.

The term “amide,” as used herein, means —C(O)NR— or —NRC(O)—, wherein Rmay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle,alkenyl, or heteroalkyl.

The term “aminoalkyl,” as used herein, means at least one amino group,as defined herein, is appended to the parent molecular moiety through analkylene group, as defined herein.

The term “amino” as used herein, means —NR_(x)R_(y), wherein R_(x) andR_(y) may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle,alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any othermoiety where amino appends together two other moieties, amino may be—NR_(x)—, wherein R_(x) may be hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heterocycle, alkenyl, or heteroalkyl.

The term “aryl” as used herein, refers to an aromatic group such as aphenyl group, or a bicyclic fused ring system. Bicyclic fused ringsystems are exemplified by a phenyl group appended to the parentmolecular moiety and fused to a cycloalkyl group, as defined herein, aphenyl group, a heteroaryl group, as defined herein, or a heterocycle,as defined herein. Representative examples of aryl include, but are notlimited to, indolyl, naphthyl, phenyl, quinolinyl, andtetrahydroquinolinyl.

The term “carboxyl” as used herein, means a carboxylic acid, or —COOH.

The term “cycloalkyl” means a monovalent saturated hydrocarbon ring or abicyclic group. Cycloalkyl groups have zero heteroatoms and zero doublebonds. Cycloalkyl groups are monocyclic, or are fused, spiro, or bridgedbicyclic ring systems. Monocyclic cycloalkyl groups contain 3 to 10carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6carbon atoms in the ring. Bicyclic cycloalkyl groups contain 8 to 12carbon atoms, preferably 9 to 10 carbon atoms in the ring. Cycloalkylgroups may be substituted or unsubstituted. Cycloalkyl groups include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

The term “cycloalkenyl,” as used herein, means a non-aromatic monocyclicor multicyclic ring system containing at least one carbon-carbon doublebond and preferably having from 5-10 carbon atoms per ring. Exemplarymonocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, andcycloheptenyl.

The term “cycloalkynyl,” as used herein, means a monocyclic ormulticyclic ring system containing at least one carbon-carbon triplebond and preferably having from 5-10 carbon atoms per ring or more than10 carbon atoms per ring.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by a halogen. Representative examples ofhaloalkyl include, but are not limited to, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,and trifluoropropyl such as 3,3,3-trifluoropropyl.

The term “halogen” or “halo” as used herein, means Cl, Br, I, or F.

The term “heteroalkyl” as used herein, means an alkyl group, as definedherein, in which at least one of the carbons of the alkyl group isreplaced with a heteroatom, such as oxygen, nitrogen, and sulfur.Representative examples of heteroalkyls include, but are not limited to,alkyl ethers, secondary and tertiary alkyl amines, amides, and alkylsulfides.

The term “heteroaryl” as used herein, refers to an aromatic monocyclicring or an aromatic bicyclic ring system containing at least oneheteroatom independently selected from the group consisting of N, O, andS. The aromatic monocyclic rings are five or six membered ringscontaining at least one heteroatom independently selected from the groupconsisting of N, O, and S. The five membered aromatic monocyclic ringshave two double bonds and the six membered six membered aromaticmonocyclic rings have three double bonds. The bicyclic heteroaryl groupsare exemplified by a monocyclic heteroaryl ring appended to the parentmolecular moiety and fused to a monocyclic cycloalkyl group, as definedherein, a monocyclic aryl group, as defined herein, a monocyclicheteroaryl group, as defined herein, or a monocyclic heterocycle, asdefined herein. Representative examples of heteroaryl include, but arenot limited to, indolyl, pyridinyl (including pyridin-2-yl,pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl,pyrazolyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl,benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl,benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl,isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl, quinazolinyl,1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, naphthyridinyl,pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl,thiazolo[5,4-d]pyrimidin-2-yl.

The term “heterocycle” or “heterocyclic” or “heterocyclyl” as usedherein means a monocyclic heterocycle, a bicyclic heterocycle(heterobicyclic), or a tricyclic heterocycle. The monocyclic heterocycleis a three-, four-, five-, six-, seven-, or eight-membered ringcontaining at least one heteroatom independently selected from the groupconsisting of O, N, and S. The three- or four-membered ring containszero or one double bond, and one heteroatom selected from the groupconsisting of O, N, and S. The five-membered ring contains zero or onedouble bond and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. The six-membered ring contains zero, one, ortwo double bonds and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. The seven- and eight-membered ringscontains zero, one, two, or three double bonds and one, two, or threeheteroatoms selected from the group consisting of O, N, and S.Representative examples of monocyclic heterocycles include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle, or a bridged monocyclicheterocycle ring system in which two non-adjacent atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or analkenylene bridge of two, three, or four carbon atoms. Representativeexamples of bicyclic heterocycles include, but are not limited to,benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non-adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1³,]decane). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heteroarylalkyl” as used herein, refers to a heteroaryl group,as defined herein, appended to the parent molecular moiety through analkylene group, as defined herein.

The term “heterocyclylalkyl” as used herein, refers to a heterocyclegroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one —OH group, isappended to the parent molecular moiety through an alkylene group, asdefined herein.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl or cycloalkyl) is indicated by the prefix“C_(x-y-)”, wherein x is the minimum and y is the maximum number ofcarbon atoms in the substituent. Thus, for example, “C₁₋₃ alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.

The term “substituted” refers to a group that may be further substitutedwith one or more non-hydrogen substituent groups. Substituent groupsinclude, but are not limited to, halogen, ═O (oxo), ═S (thioxo), cyano,nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl,alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl,arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene,aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate,and acyl.

The term “

” designates a single bond (—) or a double bond (═) or a triple bond (

).

For compounds described herein, groups and substituents thereof may beselected in accordance with permitted valence of the atoms and thesubstituents, such that the selections and substitutions result in astable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

“Amino acid” as used herein refers to naturally occurring andnon-natural synthetic amino acids, as well as amino acid analogs andamino acid mimetics that function in a manner similar to the naturallyoccurring amino acids. Naturally occurring amino acids are those encodedby the genetic code. Amino acids can be referred to herein by eithertheir commonly known three-letter symbols or by the one-letter symbolsrecommended by the IUPAC-IUB Biochemical Nomenclature Commission. Aminoacids include the side chain and polypeptide backbone portions.

The term “antagonist” refers to a molecule which blocks (e.g., reducesor prevents) a biological activity.

As used herein, the term “agonist” refers to a molecule or compound thattriggers (e.g., initiates or promotes), partially or fully enhances,stimulates, or activates one or more biological activities. An agonistmay mimic the action of a naturally occurring substance. In someembodiments, an agonist as detailed herein may mimic the action ofReelin. In some embodiments, the term refers to a compound thatactivates the Reelin signaling system. Whereas an agonist causes anaction, an antagonist blocks the action of the agonist.

The terms “control,” “reference level,” and “reference” are used hereininterchangeably. The reference level may be a predetermined value orrange, which is employed as a benchmark against which to assess themeasured result. “Control group” as used herein refers to a group ofcontrol subjects. The predetermined level may be a cutoff value from acontrol group. The predetermined level may be an average from a controlgroup. Cutoff values (or predetermined cutoff values) may be determinedby Adaptive Index Model (AIM) methodology. Cutoff values (orpredetermined cutoff values) may be determined by a receiver operatingcurve (ROC) analysis from biological samples of the patient group. ROCanalysis, as generally known in the biological arts, is a determinationof the ability of a test to discriminate one condition from another,e.g., to determine the performance of each marker in identifying apatient having CRC. A description of ROC analysis is provided in P. J.Heagerty et al. (Biometrics 2000, 56, 337-44), the disclosure of whichis hereby incorporated by reference in its entirety. Alternatively,cutoff values may be determined by a quartile analysis of biologicalsamples of a patient group. For example, a cutoff value may bedetermined by selecting a value that corresponds to any value in the25th-75th percentile range, preferably a value that corresponds to the25th percentile, the 50th percentile or the 75th percentile, and morepreferably the 75th percentile. Such statistical analyses may beperformed using any method known in the art and can be implementedthrough any number of commercially available software packages (e.g.,from Analyse-it Software Ltd., Leeds, UK; StataCorp LP, College Station,Tex.; SAS Institute Inc., Cary, N.C.). The healthy or normal levels orranges for a target or for a protein activity may be defined inaccordance with standard practice. A control may be an subject or cellwithout an agonist as detailed herein. A control may be a subject, or asample therefrom, whose disease state is known. The subject, or sampletherefrom, may be healthy, diseased, diseased prior to treatment,diseased during treatment, or diseased after treatment, or a combinationthereof.

As used herein, a disease or disorder of the central nervous system(CNS) refers to a disorder affecting either the spinal cord (e.g., amyelopathy) or brain (e.g., an encephalopathy) of a subject, which maypresent with neurological and/or psychiatric symptoms. CNS disordersinclude many various neurodegenerative diseases and psychiatricdisorders. In some embodiments, the disease or disorder is adevelopmental disorder, a cognitive disorder, a degenerative disorder, aneuropsychiatric disorder, or brain injury. In some embodiments, thedevelopmental disorder is Lissecephaly. In some embodiments, thecognitive disorder is selected from Angelman Syndrome and schizophrenia.In some embodiments, the degenerative disorder is Alzheimer's disease.In some embodiments, the neuropsychiatric disorder is selected fromschizophrenia and bipolar disorder. In some embodiments, the braininjury is traumatic brain injury (TBI). In some embodiments, the diseaseor disorder is selected from Lissecephaly, fragile X syndrome, William'ssyndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism,ischemia, hypoxia, Alzheimer's disease, Reelin deficiency,schizophrenia, bipolar disorder, neurodegeneration, traumatic braininjury, mental retardation, dementia, bipolar disorder, stroke, andage-related cognitive decline.

“Polynucleotide” as used herein can be single stranded or doublestranded, or can contain portions of both double stranded and singlestranded sequence. The polynucleotide can be nucleic acid, natural orsynthetic, DNA, genomic DNA, cDNA, RNA, or a hybrid, where thepolynucleotide can contain combinations of deoxyribo- andribo-nucleotides, and combinations of bases including uracil, adenine,thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine,and isoguanine. Polynucleotides can be obtained by chemical synthesismethods or by recombinant methods.

A “peptide” or “polypeptide” is a linked sequence of two or more aminoacids linked by peptide bonds. The polypeptide can be natural,synthetic, or a modification or combination of natural and synthetic.Peptides and polypeptides include proteins such as binding proteins,receptors, and antibodies. The terms “polypeptide”, “protein,” and“peptide” are used interchangeably herein. “Primary structure” refers tothe amino acid sequence of a particular peptide. “Secondary structure”refers to locally ordered, three dimensional structures within apolypeptide. These structures are commonly known as domains, e.g.,enzymatic domains, extracellular domains, transmembrane domains, poredomains, and cytoplasmic tail domains. “Domains” are portions of apolypeptide that form a compact unit of the polypeptide and aretypically 15 to 350 amino acids long. Exemplary domains include domainswith enzymatic activity or ligand binding activity. Typical domains aremade up of sections of lesser organization such as stretches ofbeta-sheet and alpha-helices. “Tertiary structure” refers to thecomplete three dimensional structure of a polypeptide monomer.“Quaternary structure” refers to the three dimensional structure formedby the noncovalent association of independent tertiary units. A “motif”is a portion of a polypeptide sequence and includes at least two aminoacids. A motif may be 2 to 20, 2 to 15, or 2 to 10 amino acids inlength. In some embodiments, a motif includes 3, 4, 5, 6, or 7sequential amino acids. A domain may be comprised of a series of thesame type of motif.

“Sample” or “test sample” as used herein can mean any sample in whichthe presence and/or level of a target is to be detected or determined orany sample comprising an agonist or lipoprotein receptor as detailedherein. Samples may include liquids, solutions, emulsions, orsuspensions. Samples may include a medical sample. Samples may includeany biological fluid or tissue, such as blood, whole blood, fractions ofblood such as plasma and serum, muscle, interstitial fluid, sweat,saliva, urine, tears, synovial fluid, bone marrow, cerebrospinal fluid,nasal secretions, sputum, amniotic fluid, bronchoalveolar lavage fluid,gastric lavage, emesis, fecal matter, lung tissue, peripheral bloodmononuclear cells, total white blood cells, lymph node cells, spleencells, tonsil cells, cancer cells, tumor cells, bile, digestive fluid,skin, or combinations thereof. In some embodiments, the sample comprisesan aliquot. In other embodiments, the sample comprises a biologicalfluid. Samples can be obtained by any means known in the art. The samplecan be used directly as obtained from a patient or can be pre-treated,such as by filtration, distillation, extraction, concentration,centrifugation, inactivation of interfering components, addition ofreagents, and the like, to modify the character of the sample in somemanner as discussed herein or otherwise as is known in the art.

“Subject” as used herein can mean a mammal that wants or is in need ofthe herein described agonists or methods. The subject may be a patient.The subject may be a human or a non-human animal. The subject may be amammal. The mammal may be a primate or a non-primate. The mammal can bea primate such as a human; a non-primate such as, for example, dog, cat,horse, cow, pig, mouse, rat, camel, llama, goat, rabbit, sheep, hamster,and guinea pig; or non-human primate such as, for example, monkey,chimpanzee, gorilla, orangutan, and gibbon. The subject may be of anyage or stage of development, such as, for example, an adult, anadolescent, or an infant. In some embodiments, the subject has aspecific genetic marker.

“Substantially identical” can mean that a first and second amino acidsequence are at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,98%, or 99% over a region of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800,900, 1000, 1100 amino acids.

“Treatment” or “treating,” when referring to protection of a subjectfrom a disease, means preventing, suppressing, repressing, ameliorating,or completely eliminating the disease. Preventing the disease involvesadministering a composition of the present invention to a subject priorto onset of the disease. Suppressing the disease involves administeringa composition of the present invention to a subject after induction ofthe disease but before its clinical appearance. Repressing orameliorating the disease involves administering a composition of thepresent invention to a subject after clinical appearance of the disease.

“Variant” as used herein with respect to a polynucleotide means (i) aportion or fragment of a referenced nucleotide sequence; (ii) thecomplement of a referenced nucleotide sequence or portion thereof; (iii)a polynucleotide that is substantially identical to a referencedpolynucleotide or the complement thereof; or (iv) a polynucleotide thathybridizes under stringent conditions to the referenced polynucleotide,complement thereof, or a sequences substantially identical thereto.

A “variant” can further be defined as a peptide or polypeptide thatdiffers in amino acid sequence by the insertion, deletion, orconservative substitution of amino acids, but retain at least onebiological activity. Representative examples of “biological activity”include the ability to be bound by a specific antibody or polypeptide orto promote an immune response. Variant can mean a substantiallyidentical sequence. Variant can mean a functional fragment thereof.Variant can also mean multiple copies of a polypeptide. The multiplecopies can be in tandem or separated by a linker. Variant can also meana polypeptide with an amino acid sequence that is substantiallyidentical to a referenced polypeptide with an amino acid sequence thatretains at least one biological activity. A conservative substitution ofan amino acid, i.e., replacing an amino acid with a different amino acidof similar properties (e.g., hydrophilicity, degree and distribution ofcharged regions) is recognized in the art as typically involving a minorchange. These minor changes can be identified, in part, by consideringthe hydropathic index of amino acids. See Kyte et al., J. Mol. Biol.1982, 157, 105-132. The hydropathic index of an amino acid is based on aconsideration of its hydrophobicity and charge. It is known in the artthat amino acids of similar hydropathic indexes can be substituted andstill retain protein function. In one aspect, amino acids havinghydropathic indices of ±2 are substituted. The hydrophobicity of aminoacids can also be used to reveal substitutions that would result inpolypeptides retaining biological function. A consideration of thehydrophilicity of amino acids in the context of a polypeptide permitscalculation of the greatest local average hydrophilicity of thatpolypeptide, a useful measure that has been reported to correlate wellwith antigenicity and immunogenicity, as discussed in U.S. Pat. No.4,554,101, which is fully incorporated herein by reference. Substitutionof amino acids having similar hydrophilicity values can result inpolypeptides retaining biological activity, for example immunogenicity,as is understood in the art. Substitutions can be performed with aminoacids having hydrophilicity values within ±2 of each other. Both thehydrophobicity index and the hydrophilicity value of amino acids areinfluenced by the particular side chain of that amino acid. Consistentwith that observation, amino acid substitutions that are compatible withbiological function are understood to depend on the relative similarityof the amino acids, and particularly the side chains of those aminoacids, as revealed by the hydrophobicity, hydrophilicity, charge, size,and other properties.

A variant can be a polynucleotide sequence that is substantiallyidentical over the full length of the full gene sequence or a fragmentthereof. The polynucleotide sequence can be 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or 100% identical over the full length of the gene sequence or afragment thereof. A variant can be an amino acid sequence that issubstantially identical over the full length of the amino acid sequenceor fragment thereof. The amino acid sequence can be 80%, 81%, 82%, 83%,84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, or 100% identical over the full length of the amino acidsequence or a fragment thereof.

2. REELIN

Reelin is a secreted extracellular matrix glycoprotein that helpsregulate processes of neuronal migration and positioning in thedeveloping brain by controlling cell-cell interactions. Reelin maymodulate synaptic plasticity by enhancing the induction and maintenanceof long-term potentiation, stimulate dendrite and dendritic spinedevelopment, and regulate the migration of neuroblasts generated inadult neurogenesis. Reelin may be found in, for example, the brain,spinal cord, blood, and other organs and tissues.

Full-length Reelin is a 450 kDa polypepetide. Full-length Reelin may becleaved at two sites located after domains 2 and 6—approximately betweenrepeats 2 and 3 and between repeats 6 and 7—resulting in the productionof five smaller polypeptide fragments, including a 180 kDa polypeptidefragment.

3. LIPOPROTEIN RECEPTOR

Reelin may bind to a low density lipoprotein receptor. Low densitylipoprotein receptors include, for example, VLDLR and apolipoprotein Ereceptor 2 (ApoER2). In some embodiments, the lipoprotein receptorcomprises ApoER2. In some embodiments, the lipoprotein receptorcomprises VLDLR. The lipoprotein receptors may influence braindevelopment and function. VLDLR may conduct a stop signal, while ApoER2has a role in the migration of late-born neocortical neurons. Both VLDLRand ApoER2 have in an internalization domain called the NPxY motif.After binding to the VLDLR or ApoER2 receptor, Reelin is internalizedinto the cell by endocytosis.

The interaction of Reelin with the lipoprotein receptor activatesintracellular processes. The transmission of Reelin signals through theVLDLR and/or ApoER2 lipoprotein receptors may begin with thephosphorylation of DAB1. DAB1 may bind to the intracellular portion ofthe VLDLR or ApoER2 receptor. DAB1 may be phosphorylated by two tyrosinekinases, Fyn and Src. The phosphorylated DAB1 may then cause furtheractivation of these two kinases and others, including aphosphatidylinositol-3-kinase (PI3K).

4. AGONISTS

Further provided herein are agonists of a lipoprotein receptor. Theagonist may activate a Reelin signaling pathway. The agonist mayactivate a lipoprotein receptor independently of Reelin. In someembodiments, the agonist may dimerize or cluster the lipoproteinreceptor. Activity of the agonist may be determined by measuring ormonitoring an activity or level of a polypeptide in the Reelin signalingpathway. For example, the activity of an agonist may be determined bymeasuring the level of phosphorylation of DAB1. The activity of anagonist may be determined by measuring the expression of ApoER2. Theactivity of an agonist may be determined by measuring the dimerizationof the VLDLR lipoprotein receptor, the dimerization of the ApoER2lipoprotein receptor, or a combination thereof. The receptor may includea luciferase, fluorescent polypeptide, or other label to measure andmonitor the dimerization. The activity of an agonist may be determinedby measuring or monitoring an activity or level of downstream signalinglinked to DAB-1 phosphorylation, including, for example, phosphorylationof extracellular regulated kinase (ERK), phosphoinositide 3-kinase(PI3K), Src family of Tyrosine kinases, or a combination thereof.

a. Compounds

The agonist may be a compound according to Formula I′:

or a pharmaceutically acceptable salt thereof,

wherein R¹ is independently hydrogen, halogen, hydroxyl, alkoxyl, oralkyl;

n is an integer from 0 to 5;

W is C, CH, CH₂, or O;

Q is C, CH, CH₂, N, or NH;

Z is C═O, NH, or CH₂;

Y is C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and

X is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein R² is independently hydrogen, halogen, hydroxyl, alkoxyl, oralkyl, and m is an integer from 0 to 5.

In some embodiments of Formula I′, R¹ is methoxy. In some embodiments ofFormula I′, R¹ is OH. In some embodiments of Formula I′, R¹ isisopropyl. In some embodiments of Formula I′, n is 1 or 2.

In some embodiments of Formula I′, W is O. In some embodiments ofFormula I′, W is CH.

In some embodiments of Formula I′, Q is N. In some embodiments ofFormula I′, Q is CH. In some embodiments of Formula I′, Q is CH₂.

In some embodiments of Formula I′, Z is NH. In some embodiments ofFormula I′, Z is C═O.

In some embodiments of Formula I′, Y is NH. In some embodiments ofFormula I′, Y is C═O.

In some embodiments of Formula I′, Z and Y together form a bicyclicring. In some embodiments of Formula I′, Z and Y together form aheterobicyclic ring. In some embodiments of Formula I′, Z and Y togetherform a heteroaryl ring. In some embodiments of Formula I′, Z and Ytogether form benzimidazole.

In some embodiments of Formula I′, X is aryl substituted with (R²)_(m).In some embodiments of Formula I′, X is phenyl substituted with(R²)_(m).

In some embodiments of Formula I′, R² is methyl. In some embodiments ofFormula I′, R² is Cl, I, F, or Br. In some embodiments of Formula I′, R²is Cl or I.

In some embodiments of Formula I′, m is 1 or 2.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is isopropyl, n is 1, W is CH, Q is CH, Z is C═O, Y is NH, and X isphenyl substituted with (R²)_(m), wherein R² is Cl and m is 1.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is isopropyl, n is 1, W is CH, Q is CH, Z is C═O, Y is NH, and X isphenyl substituted with (R²)_(m), wherein R² is C and m is 2.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is isopropyl, n is 1, W is CH, Q is CH, Z is C═O, Y is NH, and X isphenyl substituted with (R²)_(m), wherein R² is C═O and m is 2.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is isopropyl, n is 1, W is CH, Q is CH, Z is C═O, Y is NH, and X isphenyl substituted with (R²)_(m), wherein R² is C═O and m is 1.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is isopropyl, n is 1, W is CH, Q is CH, Z is C═O, Y is NH, and X isphenyl substituted with (R²)_(m), wherein R² is independently C═O or Iand m is 2.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is isopropyl, n is 1, W is CH, Q is CH, Z is C═O, Y is NH, and X isphenyl substituted with (R²)_(m), wherein R² is C and m is 1.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is independently OH and methoxy, n is 2, W is CH, Q is N, Z and Ytogether form benzimidazole, and X is phenyl substituted with (R²)_(m),wherein R² is Cl and m is 2.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is OH, n is 2, W is CH, Q is N, Z is NH, Y is C═O, and X is phenylsubstituted with (R²)_(m), wherein R² is methyl and m is 1.

In some embodiments, the agonist is a compound of Formula I′, wherein R¹is Cl, n is 2, W is O, Q is CH₂, Z is C═O, Y is NH, and X is phenylsubstituted with (R²)_(m), wherein R² is Cl and m is 1.

In some embodiments, compounds of Formula I′ have a structure ofFormula 1. The agonist may be a compound according to Formula I:

or a pharmaceutically acceptable salt thereof,

wherein R¹ is independently hydrogen, halogen, hydroxyl, alkoxyl, oralkyl;

n is an integer from 0 to 5;

Q is C, CH, CH₂, N, or NH;

Z is C═O, NH, or CH₂;

Y is C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and

X is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein R² is independently hydrogen, halogen, hydroxyl, alkoxyl, oralkyl, and m is an integer from 0 to 5.

In some embodiments of Formula I, R¹ is methoxy. In some embodiments ofFormula I, R¹ is OH. In some embodiments of Formula I, R¹ is isopropyl.In some embodiments of Formula I, n is 1 or 2.

In some embodiments of Formula I, Q is N. In some embodiments of FormulaI, Q is CH.

In some embodiments of Formula I, Z is NH. In some embodiments ofFormula I, Z is C═O.

In some embodiments of Formula I, Y is NH. In some embodiments ofFormula I, Y is C═O.

In some embodiments of Formula I, Z and Y together form a bicyclic ring.In some embodiments of Formula I, Z and Y together form a heterobicyclicring. In some embodiments of Formula I, Z and Y together form aheteroaryl ring. In some embodiments of Formula I, Z and Y together formbenzimidazole.

In some embodiments of Formula I, X is aryl substituted with (R²)_(m).In some embodiments of Formula I, X is phenyl substituted with (R²)_(m).

In some embodiments of Formula I, R² is methyl. In some embodiments ofFormula I, R² is Cl, I, F, or Br. In some embodiment of Formula I, R² isCl or I.

In some embodiments of Formula I, m is 1 or 2.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is isopropyl, n is 1, Q is CH, Z is C═O, Y is NH, and X is phenylsubstituted with (R²)_(m), wherein R² is Cl and m is 1.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is isopropyl, n is 1, Q is CH, Z is C═O, Y is NH, and X is phenylsubstituted with (R²)_(m), wherein R² is Cl and m is 2.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is isopropyl, n is 1, Q is CH, Z is C═O, Y is NH, and X is phenylsubstituted with (R²)_(m), wherein R² is C and m is 2.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is isopropyl, n is 1, Q is CH, Z is C═O, Y is NH, and X is phenylsubstituted with (R²)_(m), wherein R² is Cl and m is 1.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is isopropyl, n is 1, Q is CH, Z is C═O, Y is NH, and X is phenylsubstituted with (R²)_(m), wherein R² is Cl and I and m is 2.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is isopropyl, n is 1, Q is CH, Z is C═O, Y is NH, and X is phenylsubstituted with (R²)_(m), wherein R² is Cl and m is 1.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is independently OH and methoxy, n is 2, Q is N, Z and Y together formbenzimidazole, and X is phenyl substituted with (R²)_(m), wherein R² isCl and m is 2.

In some embodiments, the agonist is a compound of Formula I, wherein R¹is OH, n is 2, Q is N, Z is NH, Y is C═O, and X is phenyl substitutedwith (R²)_(m), wherein R² is methyl and m is 1.

The agonist may be a compound according to Formula II:

or a pharmaceutically acceptable salt thereof,

wherein R¹ is independently hydrogen, halogen, hydroxyl, alkoxyl, oralkyl;

n is an integer from 0 to 5;

R² is independently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; and

m is an integer from 0 to 5.

In some embodiments of Formula II, R¹ is C₁₋₄ alkyl. In some embodimentsof Formula II, R¹ is methyl, ethyl, or isopropyl.

In some embodiments of Formula II, R² is Cl, I, F, or Br. In someembodiments of Formula II, R² is Cl or I. In some embodiments of FormulaII, m is 1 or 2.

In some embodiments, the agonist is a compound of Formula II, wherein R²is Cl, m is 1, R¹ is isopropyl, and n is 1.

In some embodiments, the agonist is a compound of Formula II, wherein R²is Cl, m is 2, R¹ is isopropyl, and n is 1.

In some embodiments, the agonist is a compound of Formula II, wherein R²is Cl, m is 2, R¹ is isopropyl, and n is 1.

In some embodiments, the agonist is a compound of Formula II, wherein R²is Cl, m is 1, R¹ is isopropyl, and n is 1.

In some embodiments, the agonist is a compound of Formula II, wherein R²is independently Cl or I, m is 2, R¹ is isopropyl, and n is 1.

In some embodiments, the agonist is a compound of Formula II, wherein R²is Cl, m is 1, R¹ is isopropyl, and n is 1.

In some embodiments of Formula II, R² is Cl, I, F, or Br, and m is 1. Insome embodiments of Formula II, R² is Cl or I and m is 1.

The agonist may be a compound according to Formula III:

or a pharmaceutically acceptable salt thereof,

wherein each R¹ is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl;

n is an integer from 0 to 5; and

R² is hydrogen, halogen, hydroxyl, alkoxyl, or alkyl

In some embodiments of Formula III, R¹ is C₁₋₄ alkyl. In someembodiments of Formula III, R¹ is methyl, ethyl, or isopropyl. In someembodiments of Formula III, R¹ is isopropyl. In some embodiments ofFormula III, n is 1 or 2.

In some embodiments of Formula III, R² is Cl, I, F, or Br. In someembodiments of Formula III, R² is Cl or I. In some embodiments ofFormula III, R² is Cl.

In some embodiments, the agonist is a compound of Formula III, whereinR² is Cl, R¹ is isopropyl, and n is 1.

In some embodiments, the agonist comprises one of the followingcompounds:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the agonist does not comprise at least one of thefollowing compounds:

or a pharmaceutically acceptable salt thereof.

The compound may exist as a stereoisomer wherein asymmetric or chiralcenters are present. The stereoisomer is “R” or “S” depending on theconfiguration of substituents around the chiral carbon atom. The terms“R” and “S” used herein are configurations as defined in IUPAC 1974Recommendations for Section E, Fundamental Stereochemistry, in PureAppl. Chem., 1976, 45, 13-30. The disclosure contemplates variousstereoisomers and mixtures thereof and these are specifically includedwithin the scope of this invention. Stereoisomers include enantiomersand diastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of the compounds may be prepared syntheticallyfrom commercially available starting materials, which contain asymmetricor chiral centers or by preparation of racemic mixtures followed bymethods of resolution well-known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of amixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and optional liberation of the optically pure productfrom the auxiliary as described in Furniss, Hannaford, Smith, andTatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition(1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2)direct separation of the mixture of optical enantiomers on chiralchromatographic columns, or (3) fractional recrystallization methods.

It should be understood that the compound may possess tautomeric forms,as well as geometric isomers, and that these also constitute embodimentsof the disclosure.

The present disclosure also includes an isotopically-labeled compound,which is identical to those recited in Formulas I′ and I and II and III,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. Examples of isotopes suitable forinclusion in the compounds of the invention are hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as,but not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Substitution with heavier isotopes such asdeuterium, i.e. ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. The compound may incorporate positron-emittingisotopes for medical imaging and positron-emitting tomography (PET)studies for determining the distribution of receptors. Suitablepositron-emitting isotopes that can be incorporated in compounds ofFormulas I′ and I and II and III are ¹¹C, ¹³N, ¹⁵O, and ¹⁸F.Isotopically-labeled compounds of Formulas I′ and I and II and III cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples using appropriate isotopically-labeled reagent inplace of non-isotopically-labeled reagent.

b. Pharmaceutically Acceptable Salts

The disclosed compounds may exist as pharmaceutically acceptable salts.The term “pharmaceutically acceptable salt” refers to salts orzwitterions of the compounds which are water or oil-soluble ordispersible, suitable for treatment of disorders without undue toxicity,irritation, and allergic response, commensurate with a reasonablebenefit/risk ratio and effective for their intended use. The salts maybe prepared during the final isolation and purification of the compoundsor separately by reacting an amino group of the compounds with asuitable acid. For example, a compound may be dissolved in a suitablesolvent, such as but not limited to methanol and water and treated withat least one equivalent of an acid, like hydrochloric acid. Theresulting salt may precipitate out and be isolated by filtration anddried under reduced pressure. Alternatively, the solvent and excess acidmay be removed under reduced pressure to provide a salt. Representativesalts include acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, isethionate, fumarate, lactate, maleate, methanesulfonate,naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,glutamate, para-toluenesulfonate, undecanoate, hydrochloric,hydrobromic, sulfuric, phosphoric, and the like. The amino groups of thecompounds may also be quaternized with alkyl chlorides, bromides andiodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl,myristyl, stearyl, and the like.

Basic addition salts may be prepared during the final isolation andpurification of the disclosed compounds by reaction of a carboxyl groupwith a suitable base such as the hydroxide, carbonate, or bicarbonate ofa metal cation such as lithium, sodium, potassium, calcium, magnesium,or aluminum, or an organic primary, secondary, or tertiary amine.Quaternary amine salts can be prepared, such as those derived frommethylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine,dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine andN,N′dibenzylethylenediamine, ethylenediamine, ethanolamine,diethanolamine, piperidine, piperazine, and the like.

c. Synthesis of Compounds

Compounds as detailed herein are commercially available, for example,from Chembridge Corporation (San Diego, Calif.). Alternatively, thecompounds as detailed herein may be synthetically made by methods knownto one of skill in the art.

d. Pharmaceutical Compositions

The compounds as detailed herein may be formulated into pharmaceuticalcompositions in accordance with standard techniques well known to thoseskilled in the pharmaceutical art. The composition may comprise thecompound and a pharmaceutically acceptable carrier. The term“pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type.

The route by which the disclosed compounds are administered and the formof the composition will dictate the type of carrier to be used. Thepharmaceutical composition may be in a variety of forms, suitable, forexample, for systemic administration (e.g., oral, rectal, sublingual,buccal, implants, intranasal, intravaginal, transdermal, intravenous,intraarterial, intratumoral, intraperitoneal, or parenteral) or topicaladministration (e.g., dermal, pulmonary, nasal, aural, ocular, liposomedelivery systems, or iontophoresis). In some embodiments, thepharmaceutical composition is for administration to a subject's centralnervous system. Techniques and formulations may generally be found in“Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton,Pa.). Pharmaceutical compositions must typically be sterile and stableunder the conditions of manufacture and storage. All carriers areoptional in the compositions.

Pharmaceutically acceptable carriers include, for example, diluents,lubricants, binders, disintegrants, colorants, flavors, sweeteners,antioxidants, preservatives, glidants, solvents, suspending agents,wetting agents, surfactants, emollients, propellants, humectants,powders, pH adjusting agents, and combinations thereof.

Suitable diluents include, for example, sugars such as glucose, lactose,dextrose, and sucrose; diols such as propylene glycol; calciumcarbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol;sorbitol; cellulose; starch; and gelatin. The amount of diluent(s) in asystemic or topical composition may typically be about 50 to about 90%.

Suitable lubricants include, for example, silica, talc, stearic acid andits magnesium salts and calcium salts, calcium sulfate; and liquidlubricants such as polyethylene glycol and vegetable oils such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil, and oil oftheobroma. The amount of lubricant(s) in a systemic or topicalcomposition may typically be about 5 to about 10%.

Suitable binders include, for example, polyvinyl pyrrolidone; magnesiumaluminum silicate; starches such as corn starch and potato starch;gelatin; tragacanth; sucrose; and cellulose and its derivatives, such assodium carboxymethylcellulose, ethyl cellulose, methylcellulose,microcrystalline cellulose, and hydroxypropyl methylcellulose. Theamount of binder(s) in a systemic composition may typically be about 5to about 50%.

Suitable disintegrants include, for example, agar, alginic acid and thesodium salt thereof, effervescent mixtures, croscarmelose, crospovidone,sodium carboxymethyl starch, sodium starch glycolate, clays, and ionexchange resins. The amount of disintegrant(s) in a systemic or topicalcomposition may typically be about 0.1 to about 10%.

Suitable colorants include, for example, a colorant such as an FD&C dye.When used, the amount of colorant in a systemic or topical compositionmay typically be about 0.005 to about 0.1%.

Suitable flavors include, for example, menthol, peppermint, and fruitflavors. The amount of flavor(s), when used, in a systemic or topicalcomposition may typically be about 0.1 to about 1.0%.

Suitable sweeteners include, for example, aspartame and saccharin, or acombination thereof. The amount of sweetener(s) in a systemic or topicalcomposition may typically be about 0.001 to about 1%.

Suitable antioxidants include, for example, butylated hydroxyanisole(“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount ofantioxidant(s) in a systemic or topical composition may typically beabout 0.1 to about 5%.

Suitable preservatives include, for example, benzalkonium chloride,methyl paraben, and sodium benzoate. The amount of preservative(s) in asystemic or topical composition may typically be about 0.01 to about 5%.

Suitable glidants include, for example, silicon dioxide. The amount ofglidant(s) in a systemic or topical composition may typically be about 1to about 5%.

Suitable solvents include, for example, water, isotonic saline, ethyloleate, glycerine, castor oils, hydroxylated castor oils, alcohols suchas ethanol or isopropanol, methylene chloride, ethylene glycol monoethylether, diethylene glycol monobutyl ether, diethylene glycol monoethylether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, andphosphate buffer solutions, and combinations thereof. The amount ofsolvent(s) in a systemic or topical composition is typically from about0 to about 100%, or 0% to about 95%.

Suitable suspending agents include, for example, AVICEL RC-591 (from FMCCorporation of Philadelphia, Pa.) and sodium alginate. The amount ofsuspending agent(s) in a systemic or topical composition may typicallybe about 1 to about 8%.

Suitable surfactants include, for example, lecithin, Polysorbate 80, andsodium lauryl sulfate, and the TWEENS from Atlas Powder Company ofWilmington, Del. Suitable surfactants include those disclosed in theC.T.F.A. Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington'sPharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon'sVolume 1, Emulsifiers & Detergents, 1994, North American Edition, pp.236-239. The amount of surfactant(s) in the systemic or topicalcomposition may typically be about 0.1% to about 5%.

Suitable emollients include, for example, stearyl alcohol, glycerylmonoricinoleate, glyceryl monostearate, propane-1,2-diol,butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearicacid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyllaurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol,cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropylpalmitate, isopropyl stearate, butyl stearate, polyethylene glycol,triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil,castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butylmyristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryllactate, myristyl lactate, decyl oleate, myristyl myristate, andcombinations thereof. Specific emollients for skin include stearylalcohol and polydimethylsiloxane. The amount of emollient(s) in askin-based topical composition may typically be about 5% to about 95%.

Suitable propellants include, for example, propane, butane, isobutane,dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.The amount of propellant in a topical composition may be about 0% toabout 95%.

Suitable humectants include, for example, glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,gelatin, and combinations thereof. The amount of humectant in a topicalcomposition may be about 0% to about 95%.

Suitable powders include, for example, beta-cyclodextrins, hydroxypropylcyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums,colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammoniumsmectites, trialkyl aryl ammonium smectites, chemically-modifiedmagnesium aluminum silicate, organically-modified Montmorillonite clay,hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodiumcarboxymethyl cellulose, ethylene glycol monostearate, and combinationsthereof. The amount of powder(s) in a topical composition may typicallybe 0% to 95%.

Suitable pH adjusting additives include, for example, HCl or NaOH inamounts sufficient to adjust the pH of a topical pharmaceuticalcomposition.

In some embodiments, the pharmaceutically acceptable carrier is a sugarsuch as lactose, glucose, and sucrose. In some embodiments, thepharmaceutically acceptable carrier is a starch such as, for example,corn starch and potato starch. In some embodiments, the pharmaceuticallyacceptable carrier is cellulose and its derivatives such as, but notlimited to, sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate.

In some embodiments, the pharmaceutically acceptable carrier is powderedtragacanth, malt, gelatin, or talc. In some embodiments, thepharmaceutically acceptable carrier is an excipient such as, but notlimited to, cocoa butter and suppository waxes. In some embodiments, thepharmaceutically acceptable carrier is oil such as, but not limited to,peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, cornoil and soybean oil. In some embodiments, the pharmaceuticallyacceptable carrier is a glycol, such as propylene glycol. In someembodiments, the pharmaceutically acceptable carrier is an ester suchas, but not limited to, ethyl oleate and ethyl laurate. In someembodiments, the pharmaceutically acceptable carrier is an agar. In someembodiments, the pharmaceutically acceptable carrier is a bufferingagent such as, but not limited to, magnesium hydroxide and aluminumhydroxide. In some embodiments, the pharmaceutically acceptable carrieris alginic acid, pyrogen-free water, isotonic saline, Ringer's solution,ethyl alcohol, or a phosphate buffer solution. In some embodiments, thepharmaceutically acceptable carrier is a non-toxic compatible lubricantsuch as, but not limited to, sodium lauryl sulfate and magnesiumstearate.

Compositions for oral administration can have various dosage forms. Forexample, solid forms include tablets, capsules, granules, and bulkpowders. Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed. Tablets typicallyinclude an active component, and a carrier comprising ingredientsselected from diluents, lubricants, binders, disintegrants, colorants,flavors, sweeteners, glidants, and combinations thereof. Capsules(including implants, time release, and sustained release formulations)typically include a compound (e.g., a compound of Formula I′ or I or IIor III), and a carrier including one or more diluents disclosed above ina capsule comprising gelatin. Granules typically comprise a compound,and preferably glidants such as silicon dioxide to improve flowcharacteristics. Implants can be of the biodegradable or thenon-biodegradable type.

Compositions for oral administration can have solid forms. Solid oralcompositions may be coated by conventional methods, typically with pH ortime-dependent coatings, such that a disclosed compound is released inthe gastrointestinal tract in the vicinity of the desired application,or at various points and times to extend the desired action. Thecoatings typically include one or more components selected from thegroup consisting of cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose,EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany),waxes, and shellac.

Compositions for oral administration can have liquid forms. For example,suitable liquid forms include aqueous solutions, emulsions, suspensions,solutions reconstituted from non-effervescent granules, suspensionsreconstituted from non-effervescent granules, effervescent preparationsreconstituted from effervescent granules, elixirs, tinctures, syrups,and the like. Liquid orally administered compositions typically includea compound and a carrier, namely, a carrier selected from diluents,colorants, flavors, sweeteners, preservatives, solvents, suspendingagents, and surfactants. Peroral liquid compositions preferably includeone or more ingredients selected from colorants, flavors, andsweeteners.

Compositions for topical administration can be applied locally to theskin and may be in any form including solids, solutions, oils, creams,ointments, gels, lotions, shampoos, leave-on and rinse-out hairconditioners, milks, cleansers, moisturizers, sprays, skin patches, andthe like. The carrier of the topical composition preferably aidspenetration of the compounds into the skin. In the topical compositions,the carrier includes a topical carrier. Suitable topical carriers caninclude one or more ingredients selected from phosphate buffered saline,isotonic water, deionized water, monofunctional alcohols, symmetricalalcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethylisosorbide, castor oil, combinations thereof, and the like. Moreparticularly, carriers for skin applications may include propyleneglycol, dimethyl isosorbide, and water, and even more particularly,phosphate buffered saline, isotonic water, deionized water,monofunctional alcohols, and symmetrical alcohols. The carrier of atopical composition may further include one or more ingredients selectedfrom emollients, propellants, solvents, humectants, thickeners, powders,fragrances, pigments, and preservatives, all of which are optional.

Although the amounts of components in the compositions may varydepending on the type of composition prepared, in general, systemiccompositions may include 0.01% to 50% of a compound (e.g., a compound ofFormula I′ or I or II or Ill) and 50% to 99.99% of one or more carriers.Compositions for parenteral administration may typically include 0.1% to10% of a compound and 90% to 99.9% of one or more carriers. Oral dosageforms may include, for example, at least about 5%, or about 25% to about50% of a compound. The oral dosage compositions may include about 50% toabout 95% of carriers, or from about 50% to about 75% of carriers. Theamount of the carrier employed in conjunction with a disclosed compoundis sufficient to provide a practical quantity of composition foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references: ModernPharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

e. Administration

The compounds as detailed herein, or the pharmaceutical compositionscomprising the same, may be administered to a subject. Such compositionscomprising a compound can be administered in dosages and by techniqueswell known to those skilled in the medical arts taking intoconsideration such factors as the age, sex, weight, and condition of theparticular subject, and the route of administration.

The compound can be administered prophylactically or therapeutically. Inprophylactic administration, the compound can be administered in anamount sufficient to induce a response. In therapeutic applications, thecompounds are administered to a subject in need thereof in an amountsufficient to elicit a therapeutic effect. An amount adequate toaccomplish this is defined as “therapeutically effective amount.”Amounts effective for this use will depend on, e.g., the particularcomposition of the compound regimen administered, the manner ofadministration, the stage and severity of the disease, the general stateof health of the patient, and the judgment of the prescribing physician.A therapeutically effective amount is also one in which any toxic ordetrimental effects of a compound of the invention (e.g., a compound ofFormula I′ or I or II or III) are outweighed by the therapeuticallybeneficial effects. A “prophylactically effective amount” refers to anamount effective, at dosages and for periods of time necessary, toachieve the desired prophylactic result. Typically, since a prophylacticdose is used in subjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

For example, a therapeutically effective amount of a compound of FormulaI′ or I or II or Ill, may be about 1 mg/kg to about 1000 mg/kg, about 5mg/kg to about 950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15mg/kg to about 850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25mg/kg to about 750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35mg/kg to about 650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45mg/kg to about 550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55mg/kg to about 450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65mg/kg to about 350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75mg/kg to about 250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85mg/kg to about 150 mg/kg, and about 90 mg/kg to about 100 mg/kg.

The compound can be administered by methods well known in the art asdescribed in Donnelly et al. (Ann. Rev. Immunol. 1997, 15, 617-648);Felgner et al. (U.S. Pat. No. 5,580,859, issued Dec. 3, 1996); Felgner(U.S. Pat. No. 5,703,055, issued Dec. 30, 1997); and Carson et al. (U.S.Pat. No. 5,679,647, issued Oct. 21, 1997), the contents of all of whichare incorporated herein by reference in their entirety. The compound canbe complexed to particles or beads that can be administered to anindividual, for example, using a vaccine gun. One skilled in the artwould know that the choice of a pharmaceutically acceptable carrier,including a physiologically acceptable compound, depends, for example,on the route of administration.

The compound can be delivered via a variety of routes. Typical deliveryroutes include parenteral administration, e.g., intradermal,intramuscular or subcutaneous delivery. Other routes include oraladministration, intranasal, intravaginal, transdermal, intravenous,intraarterial, intratumoral, intraperitoneal, and epidermal routes. Insome embodiments, the compound is administered intravenously,intraarterially, or intraperitoneally to the subject. In someembodiments, the compound is administered to the central nervous systemof the subject. In some embodiments, the compound is administered to thesubject orally.

5. METHODS

a. Methods of Treating a Disease or Disorder

Provided herein are methods of treating a disease or disorder in asubject in need thereof. In some embodiments, the methods includeadministering to the subject an agonist of a lipoprotein receptor asdetailed herein. In some embodiments, the disease or disorder is of thecentral nervous system. In some embodiments, the disease or disorder isa developmental disorder, a cognitive disorder, a degenerative disorder,a neuropsychiatric disorder, or brain injury. In some embodiments, thedevelopmental disorder is Lissecephaly. In some embodiments, thecognitive disorder is selected from Angelman Syndrome and schizophrenia.In some embodiments, the degenerative disorder is Alzheimer's disease.In some embodiments, the neuropsychiatric disorder is selected fromschizophrenia and bipolar disorder. In some embodiments, the braininjury is traumatic brain injury (TBI). In some embodiments, the diseaseor disorder is selected from Lissecephaly, fragile X syndrome, William'ssyndrome, Rett syndrome, Down's syndrome, Angelman syndrome, autism,ischemia, hypoxia, Alzheimer's disease, Reelin deficiency,schizophrenia, bipolar disorder, neurodegeneration, traumatic braininjury, mental retardation, dementia, bipolar disorder, and stroke.

b. Methods of Improving Cognitive Function

Provided herein are methods of improving cognitive function in a subjectin need thereof. In some embodiments, the methods include administeringto the subject an agonist of a lipoprotein receptor as detailed herein.

c. Methods of Increasing Dendritic Spine Density

Provided herein are methods of increasing dendritic spine density in asubject in need thereof. In some embodiments, the methods includeadministering to the subject an agonist of a lipoprotein receptor asdetailed herein.

d. Methods of Improving Associative Learning

Provided herein are methods of improving associative learning in asubject in need thereof. In some embodiments, the methods includeadministering to the subject an agonist of a lipoprotein receptor asdetailed herein.

e. Methods of Improving Spatial Learning

Provided herein are methods of improving spatial learning in a subjectin need thereof. In some embodiments, the methods include administeringto the subject an agonist of a lipoprotein receptor as detailed herein.

f. Methods of Improving Long-Term Potentiation of Neurons

Provided herein are methods of improving long-term potentiation ofneurons in a subject in need thereof. In some embodiments, the methodsinclude administering to the subject an agonist of a lipoproteinreceptor as detailed herein.

g. Methods of Activating a Lipoprotein Receptor

Provided herein are methods of activating a lipoprotein receptor in asubject in need thereof. In some embodiments, the methods includeadministering to the subject an agonist of a lipoprotein receptor asdetailed herein.

6. EXAMPLES Example 1 Compound Screening with ApoER2 Luciferase Assay

Reelin is able to signal through ApoER2 and VLDLR by clustering thereceptors. Receptor clustering results in Dab1 activation and isresponsible for the modulation of LTP in wild-type acute hippocampalslices. The ApoER2 luciferase assay was used to measure ApoER2dimerization. This system used an ApoER2-luciferase fusion protein inwhich ApoER2 was coupled with either the N- or C-terminus portion ofluciferase. Upon receptor clustering, the N- and C-terminus portions ofluciferase combined to produce a quantifiable fluorescent signal. As acontrol, all cells were transfected with a Renilla florescent proteinthat quantified the number of cells in the testing well. The ratio ofluciferase florescence to Renilla florescence was used to determine theeffect of small molecules. The ApoER2 luciferase assay (FIG. 3) was usedto identify small molecules that mimic the actions of Reelin to activatethe Reelin signaling system.

The CNS-Set Library was purchased from ChemBridge® and consisted of35,000 small molecule compounds. The effects of each compound on Reelinsignaling were tested in the absence or presence of purified Reelingwith the ApoER2 luciferase assay in a 96-well plate. The assay was usedto identify agonists of ApoER2 clustering and luciferase activity andwas not particularly sensitive for identifying antagonists of receptorclustering.

Approximately 2,700 compounds were tested and 4 unique compounds wereidentified having significant activation properties in the ApoER2luciferase assay. Each of the 4 compounds had positive results in theabsence of Reelin, suggesting each compound is a direct agonist forApoER2 clustering and not an allosteric modulator of Reelin-inducedsignaling. The 4 compounds were designated Relact02 (1), Relact03 (7),Relact04 (9), and Relact05 (6), as detailed above. In addition, anegative control compound (E02, ethyl5-[(benzylamino)carbonyl]-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate)showed no luciferase activity.

Each of Relact02, Relact03, Relact04, and Relact05 showed a doseresponse in the ApoER2 luciferase assay (FIG. 4A, FIG. 4B, FIG. 4C, FIG.4D). Relact02 and Relact03 show a time course at the optimumconcentration (FIG. 5A, FIG. 5B).

Example 2 Further Studies with Relact02

Relact02 was tested for inducing dimerization of ApoER2 using luciferaseas a reporter. Shown in FIG. 1A is a dose response curve assessingluciferase activity. Activity was determined by dimerization of twoApoER2 receptors fused with a luciferase enzyme reporter at the N- orC-terminal region. The control was a compound with structure similar tobut different from Relact02. Shown in FIG. 1B is a time course for theluciferase assay using 5 μM of Relact02 or control molecule. Shown inFIG. 1C is a time course using 5 μM Relact02 alone (black bars) or inthe presence of the Reelin protein (gray bars). Relact02 induceddimerization of ApoER2 independently of Reelin.

To confirm this was not simply an artifact showing positive results inour ApoER2 luciferase assay, Relact02 was administered to neuronalprimary cell cultures. Primary neuronal cell cultures were treated with5 μM of control E02 or Relact02 for 1 hour. Treated cultures were probedfor an increase in ApoER2 expression, which is an indication of ApoER2activation and internalization, as well probing for DAB-1phosphorylation. As shown in FIG. 2, the results indicated Dab-1phosphorylation and up regulation of ApoER2 recycling with Relact02,which demonstrated specific activation of the Reelin pathway byRelact02. These biochemical changes can only occur through ApoER2activation and dimerization. Relact02 induced Dab-1 phosphorylation andup regulation of ApoER2 recycling independently of the Reelin protein.

Example 3 Culture Cell Signaling Assay

With the ApoER2 luciferase assay, the amount of Receptor clustering canbe seen. However, it is unknown whether clustering can occur with anunaltered ApoER2 receptor. ApoER2 is highly expressed in the CNS, andprimary neuronal cultures show intact AppoER2 and the downstreamintracellular adapter protein Dab-1 (FIG. 6A, FIG. B). There is also aconfirmed signal transduction system in cultures linking Dab-1activation to ERK and AKT, as well as changings in ApoER2 expression. Totest the ability of certain compounds (Relact02, Relact03, Relact04, andRelact05) to activate an in vitro Reelin signaling system, we appliedthe compounds to mouse neuronal primary cultures for 2 hours andperformed Western analysis to determine the activation of downstreamReelin receptor signaling pathways (Dab1, ERK, and AKT) (FIG. 7A, FIG.7B, FIG. 7C, FIG. 7D)

Example 4 Studies in Hippocampal Slices

The biochemical activity of Relact02 in hippocampal slices as a resultof induced Reelin was examined. The results are shown in FIG. 8.

Other compounds (Relact03, Relact04, and Relact05) will be testedsimilarly.

Example 5 Control Studies

We sought to determine if analogs of Relact02 and Relact05 could impartsimilar ApoER2 clustering using the ApoER2 luciferase assay. The analogswere identified by ChemBridge (San Diego, Calif.) as the most similarcompounds to Relact02 and are shown below with information in TABLE 1.

TABLE 1 Compound LogS Rotatable ID MW Formula LogP W Bonds tPSA hDonhAcc Form (2) 334 C₁₈H₁₇Cl₂NO 6.01 −6.77 3 29.1 1 1 Solid 6847970 (3)334 C₁₈H₁₇Cl₂NO 5.88 −6.66 3 29.1 1 1 Solid 5278590 (4) 300 C₁₈H₁₈CINO6.06 −6.56 3 29.1 1 1 Solid 5263004 (5) 426 C₁₈H₁₇CINO 6.42 −7.79 3 29.11 1 Solid 6918349

It was found that at a 10 μM concentration, the analogs—each ofcompounds (2), (3), (4), and (5)—did not show changes in firefly/renillaratios in the ApoER2 luciferase assay (FIG. 9A, FIG. 9B).

The foregoing description of the specific aspects will so fully revealthe general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific aspects, without undueexperimentation, without departing from the general concept of thepresent disclosure. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed aspects, based on the teaching and guidance presented herein.It is to be understood that the phraseology or terminology herein is forthe purpose of description and not of limitation, such that theterminology or phraseology of the present specification is to beinterpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present disclosure should not be limited byany of the above-described exemplary aspects, but should be defined onlyin accordance with the following claims and their equivalents.

All publications, patents, patent applications, and/or other documentscited in this application are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent, patent application, and/or other document wereindividually indicated to be incorporated by reference for all purposes.

For reasons of completeness, various aspects of the invention are setout in the following numbered clauses:

Clause 1. A method of treating a disease or disorder in a subject inneed thereof, the method comprising administering to the subject anagonist of a lipoprotein receptor.

Clause 2. A method of improving cognitive function in a subject in needthereof, the method comprising administering to the subject an agonistof a lipoprotein receptor.

Clause 3. A method of increasing dendritic spine density in a subject inneed thereof, the method comprising administering to the subject anagonist of a lipoprotein receptor.

Clause 4. A method of improving associative learning in a subject inneed thereof, the method comprising administering to the subject anagonist of a lipoprotein receptor.

Clause 5. A method of improving spatial learning in a subject in needthereof, the method comprising administering to the subject an agonistof a lipoprotein receptor.

Clause 6. A method of improving long-term potentiation of neurons in asubject in need thereof, the method comprising administering to thesubject an agonist of a lipoprotein receptor.

Clause 7. The method of any one of clauses 1-6, wherein the lipoproteinreceptor is selected from ApoER2 and VLDLR.

Clause 8. The method of clause 1, wherein the disease or disorder is ofthe central nervous system.

Clause 9. The method of clause 8, wherein the disease or disorder is adevelopmental disorder, a cognitive disorder, a degenerative disorder, aneuropsychiatric disorder, or brain injury.

Clause 10. The method of clause 9, wherein the developmental disorder isLissecephaly.

Clause 11. The method of clause 9, wherein the cognitive disorder isselected from Angelman Syndrome and schizophrenia.

Clause 12. The method of clause 9, wherein the degenerative disorder isAlzheimer's disease.

Clause 13. The method of clause 9, wherein the neuropsychiatric disorderis selected from schizophrenia and bipolar disorder.

Clause 14. The method of clause 9, wherein the brain injury is traumaticbrain injury (TBI).

Clause 15. The method of clause 8, wherein the disease or disorder isselected from Lissecephaly, fragile X syndrome, William's syndrome, Rettsyndrome, Down's syndrome, Angelman syndrome, autism, ischemia, hypoxia,Alzheimer's disease, Reelin deficiency, schizophrenia, bipolar disorder,neurodegeneration, traumatic brain injury, mental retardation, dementia,bipolar disorder, and stroke.

Clause 16. A method of treating a central nervous system disease ordisorder by activating the Reelin signaling system in a subject in needthereof, the method comprising administering to the subject an effectiveamount of a small molecule agonist of a lipoprotein receptor.

Clause 17. The method of any one of clauses 1-16, wherein the agonistcomprises a compound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;

or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.

Clause 18. A method of activating a lipoprotein receptor in a subject inneed thereof, the method comprising administering to the subject acompound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;

or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof; wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.

Clause 19. The method of clause 18, wherein the lipoprotein receptor isselected from ApoER2 and VLDLR.

Clause 20. An agonist of ApoER2 or VLDLR, wherein the agonist is acompound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;

or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.

Clause 21. A compound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;

or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5;

or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5;

or Formula III:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.

Clause 22. A pharmaceutical composition comprising the compound ofclause 21.

Clause 23. The composition of clause 22, further comprising a carrierfor oral, intranasal, intravaginal, transdermal, intravenous,intraarterial, intratumoral, intraperitoneal, or topical administration.

Clause 24. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I′, and wherein R1is methoxy, OH, or isopropyl.

Clause 25. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I′, and wherein Zand Y together form a heteroaryl ring.

Clause 26. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I′, and wherein Zand Y together form benzimidazole.

Clause 27. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I′, and wherein Xis phenyl substituted with (R2)m.

Clause 28. The method or agonist or compound of clause 27, wherein atleast one R2 is methyl.

Clause 29. The method or agonist or compound of clause 27, wherein atleast one R2 is Cl or I.

Clause 30. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I, and wherein R1is methoxy, OH, or isopropyl.

Clause 31. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I, and wherein Zand Y together form a heteroaryl ring.

Clause 32. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I, and wherein Zand Y together form benzimidazole.

Clause 33. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula I, and wherein X isphenyl substituted with (R2)m.

Clause 34. The method or agonist or compound of clause 33, wherein atleast one R2 is methyl.

Clause 35. The method or agonist or compound of clause 33, wherein atleast one R2 is Cl or I.

Clause 36. The method or agonist or compound of any one of clauses17-23, wherein the agonist or compound is of Formula II, and wherein R1is C1-4 alkyl.

Clause 37. The method or agonist or compound of clause 36, wherein R1 ismethyl, ethyl, or isopropyl.

Clause 38. The method or agonist or compound or composition of any oneof clauses 17-23, wherein the agonist or compound is of Formula II, andwherein R2 is Cl or I.

Clause 39. The method or agonist or compound or composition of any oneof clauses 17-23, wherein the agonist or compound is of Formula I′,wherein R1 is Cl, n is 2, W is O, Q is CH2, Z is C═O, Y is NH, and X isphenyl substituted with (R2)m, wherein R2 is C and m is 1.

Clause 40. The method or agonist or compound or composition of any oneof clauses 17-23, wherein the agonist or compound is of Formula III,wherein R1 is methyl, ethyl, or isopropyl.

Clause 41. The method or agonist or compound or composition of any oneof clauses 17-23, wherein the agonist or compound is of Formula III,wherein R1 is isopropyl.

Clause 42. The method or agonist or compound or composition of any oneof clauses 40-41, wherein n is 1 or 2.

Clause 43. The method or agonist or compound or composition of any oneof clauses 17-23, wherein the agonist or compound is of Formula III,wherein R2 is Cl.

Clause 44. The method or agonist or compound or composition of any oneof clauses 17-23, wherein the agonist or compound is of Formula III,wherein R2 is Cl, R1 is isopropyl, and n is 1.

Clause 45. The method or agonist or compound or composition of any oneof clauses 17-23, wherein the agonist or compound is selected from thefollowing:

or a pharmaceutically acceptable salt thereof.

1. A method of treating a disease or disorder in a subject in needthereof, the method comprising administering to the subject an agonistof a lipoprotein receptor.
 2. A method of improving cognitive functionin a subject in need thereof, the method comprising administering to thesubject an agonist of a lipoprotein receptor.
 3. A method of increasingdendritic spine density in a subject in need thereof, the methodcomprising administering to the subject an agonist of a lipoproteinreceptor.
 4. A method of improving associative learning in a subject inneed thereof, the method comprising administering to the subject anagonist of a lipoprotein receptor.
 5. A method of improving spatiallearning in a subject in need thereof, the method comprisingadministering to the subject an agonist of a lipoprotein receptor.
 6. Amethod of improving long-term potentiation of neurons in a subject inneed thereof, the method comprising administering to the subject anagonist of a lipoprotein receptor.
 7. The method of any one of claims1-6, wherein the lipoprotein receptor is selected from ApoER2 and VLDLR.8. The method of claim 1, wherein the disease or disorder is of thecentral nervous system.
 9. The method of claim 8, wherein the disease ordisorder is a developmental disorder, a cognitive disorder, adegenerative disorder, a neuropsychiatric disorder, or brain injury. 10.The method of claim 9, wherein the developmental disorder isLissecephaly.
 11. The method of claim 9, wherein the cognitive disorderis selected from Angelman Syndrome and schizophrenia.
 12. The method ofclaim 9, wherein the degenerative disorder is Alzheimer's disease. 13.The method of claim 9, wherein the neuropsychiatric disorder is selectedfrom schizophrenia and bipolar disorder.
 14. The method of claim 9,wherein the brain injury is traumatic brain injury (TBI).
 15. The methodof claim 8, wherein the disease or disorder is selected fromLissecephaly, fragile X syndrome, William's syndrome, Rett syndrome,Down's syndrome, Angelman syndrome, autism, ischemia, hypoxia,Alzheimer's disease, Reelin deficiency, schizophrenia, bipolar disorder,neurodegeneration, traumatic brain injury, mental retardation, dementia,bipolar disorder, and stroke.
 16. A method of treating a central nervoussystem disease or disorder by activating the Reelin signaling system ina subject in need thereof, the method comprising administering to thesubject an effective amount of a small molecule agonist of a lipoproteinreceptor.
 17. The method of any one of claims 1-16, wherein the agonistcomprises a compound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5; or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5; or FormulaIII:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.
 18. A method of activating a lipoprotein receptor in a subject inneed thereof, the method comprising administering to the subject acompound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5; or Formula II:

or a pharmaceutically acceptable salt thereof; wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5; or FormulaIII:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.
 19. The method of claim 18, wherein the lipoprotein receptor isselected from ApoER2 and VLDLR.
 20. An agonist of ApoER2 or VLDLR,wherein the agonist is a compound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5; or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5; or FormulaIII:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.
 21. A compound according to Formula I′:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; W is C, CH, CH₂, or O; Q is C, CH, CH₂, N, or NH; Zis C═O, NH, or CH₂; Y is C═O, NH, or CH₂, or Z and Y may together form abicyclic ring; and X is cycloalkyl, cycloalkenyl, cycloalkynyl,heterocyclyl, aryl, or heteroaryl, and may be unsubstituted orsubstituted with (R²)_(m), wherein each R² is independently hydrogen,halogen, hydroxyl, alkoxyl, or alkyl, and m is an integer from 0 to 5;or Formula I:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; Q is C, CH, CH₂, N, or NH; Z is C═O, NH, or CH₂; Yis C═O, NH, or CH₂, or Z and Y may together form a bicyclic ring; and Xis cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, orheteroaryl, and may be unsubstituted or substituted with (R²)_(m),wherein each R² is independently hydrogen, halogen, hydroxyl, alkoxyl,or alkyl, and m is an integer from 0 to 5; or Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; each R² is independently hydrogen, halogen,hydroxyl, alkoxyl, or alkyl; and m is an integer from 0 to 5; or FormulaIII:

or a pharmaceutically acceptable salt thereof, wherein each R¹ isindependently hydrogen, halogen, hydroxyl, alkoxyl, or alkyl; n is aninteger from 0 to 5; and R² is hydrogen, halogen, hydroxyl, alkoxyl, oralkyl.
 22. A pharmaceutical composition comprising the compound of claim21.
 23. The composition of claim 22, further comprising a carrier fororal, intranasal, intravaginal, transdermal, intravenous, intraarterial,intratumoral, intraperitoneal, or topical administration.
 24. The methodor agonist or compound of any one of claims 17-23, wherein the agonistor compound is of Formula I′, and wherein R¹ is methoxy, OH, orisopropyl.
 25. The method or agonist or compound of any one of claims17-23, wherein the agonist or compound is of Formula I′, and wherein Zand Y together form a heteroaryl ring.
 26. The method or agonist orcompound of any one of claims 17-23, wherein the agonist or compound isof Formula I′, and wherein Z and Y together form benzimidazole.
 27. Themethod or agonist or compound of any one of claims 17-23, wherein theagonist or compound is of Formula I′, and wherein X is phenylsubstituted with (R²)_(m).
 28. The method or agonist or compound ofclaim 27, wherein at least one R² is methyl.
 29. The method or agonistor compound of claim 27, wherein at least one R² is Cl or I.
 30. Themethod or agonist or compound of any one of claims 17-23, wherein theagonist or compound is of Formula I, and wherein R¹ is methoxy, OH, orisopropyl.
 31. The method or agonist or compound of any one of claims17-23, wherein the agonist or compound is of Formula I, and wherein Zand Y together form a heteroaryl ring.
 32. The method or agonist orcompound of any one of claims 17-23, wherein the agonist or compound isof Formula I, and wherein Z and Y together form benzimidazole.
 33. Themethod or agonist or compound of any one of claims 17-23, wherein theagonist or compound is of Formula I, and wherein X is phenyl substitutedwith (R²)_(m).
 34. The method or agonist or compound of claim 33,wherein at least one R² is methyl.
 35. The method or agonist or compoundof claim 33, wherein at least one R² is Cl or I.
 36. The method oragonist or compound of any one of claims 17-23, wherein the agonist orcompound is of Formula II, and wherein R¹ is C₁₋₄ alkyl.
 37. The methodor agonist or compound of claim 36, wherein R¹ is methyl, ethyl, orisopropyl.
 38. The method or agonist or compound or composition of anyone of claims 17-23, wherein the agonist or compound is of Formula II,and wherein R² is Cl or I.
 39. The method or agonist or compound orcomposition of any one of claims 17-23, wherein the agonist or compoundis of Formula I′, wherein R¹ is Cl, n is 2, W is O, Q is CH₂, Z is C═O,Y is NH, and X is phenyl substituted with (R²)_(m), wherein R² is Cl andm is
 1. 40. The method or agonist or compound or composition of any oneof claims 17-23, wherein the agonist or compound is of Formula II,wherein R¹ is methyl, ethyl, or isopropyl.
 41. The method or agonist orcompound or composition of any one of claims 17-23, wherein the agonistor compound is of Formula II, wherein R¹ is isopropyl.
 42. The method oragonist or compound or composition of any one of claims 40-41, wherein nis 1 or
 2. 43. The method or agonist or compound or composition of anyone of claims 17-23, wherein the agonist or compound is of Formula III,wherein R² is Cl.
 44. The method or agonist or compound or compositionof any one of claims 17-23, wherein the agonist or compound is ofFormula III, wherein R² is Cl, R¹ is isopropyl, and n is
 1. 45. Themethod or agonist or compound or composition of any one of claims 17-23,wherein the agonist or compound is selected from the following:

or a pharmaceutically acceptable salt thereof.